tbuckley/cabot-search huggingface dataset:
Abstract 4433: Galectin-3 synergizes with CD47 to suppress phagocytosis and T cell immunity in peritoneal metastases of gastric adenocarcinoma
Authors: Yibo Fan, Shumei Song, Yuan Li, Shilpa Dhar, Jiankang Jin, Xiaodao Yao, Ruiping Wang, Ailing Wang, Melissa Pool Pizzi, Jingjing Wu, Katsuhiro Yoshimura, Lang Ma, Samir Hanash, George Calin, Linghua Wang, Michael Curran, Jaffer Ajani
Journal: Cancer Research (2023)

Abstract Peritoneal metastasis (PC), the common sites of gastric adenocarcinoma (GAC) metastasis, remains resistant to therapies available in the clinics and new target is strived to be found. CD47 is one of the major players in conveying the “don’t eat me” signal upon binding its receptor SIRPα on myeloid cells which evade innate immune responses. Previously clinical studies on the blockade of CD47 alone resulted in limited clinical benefits suggesting that other target(s) must be inhibited simultaneously with CD47 for gaining advantage. Here, we found that CD47 was highly expressed on peritoneal malignant cells and its overexpression was a poor prognosticator. Additionally, we observed that Galectin-3 (Gal-3) was highly enriched in tumor cluster and was positively correlated with CD47 expression in short survival of patients revealed by scRNA-seq and metastatic GAC samples. Moreover, we found double positive of Gal-3 and CD47 significantly associated with diffuse type, poor differentiation, and tumor relapse. Mechanistically, Depletion of Gal-3 in mouse tumor and human tumor cells reduced the levels of CD47 through inhibition c-Myc expression and its binding to the promoter of CD47. Additionally, tumor-derived Gal-3 were found critical for tumor progression accompanied with protected GAC cells from phagocytosis by macrophages. Gal-3 deficiency resulted in a marked reduction in M2 macrophages and elevated T cell effector activity. Dual blockade of Gal-3 and CD47 significantly decreased tumor growth by promoted phagocytosis, repolarization of macrophage and boosted T cell immune responses in the tumor microenvironment. Our data uncover that Gal-3 synergizes with CD47 to suppress phagocytosis and orchestrates immunosuppressed milieu in the tumor microenvironment warrants combination therapeutic strategy in GAC patients with peritoneal metastases. Citation Format: Yibo Fan, Shumei Song, Yuan Li, Shilpa Dhar, Jiankang Jin, Xiaodao Yao, Ruiping Wang, Ailing Wang, Melissa Pool Pizzi, Jingjing Wu, Katsuhiro Yoshimura, Lang Ma, Samir Hanash, George Calin, Linghua Wang, Michael Curran, Jaffer Ajani. Galectin-3 synergizes with CD47 to suppress phagocytosis and T cell immunity in peritoneal metastases of gastric adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4433.
Abstract 5972: CDK1 bridges NF-kB and b-catenin signaling in response to H. pylori infection in gastric tumorigenesis
Authors: Marwah M. Al-Mathkour, Shoumin Zhu, Longlong Cao, Shayan Khalafi, Zheng Chen, Julio Poveda, Dunfa Peng, Heng Lu, Mohammed Soutto, Tianling Hu, Oliver McDonalnd, Alexander Zaika, Wael El-Rifai
Journal: Cancer Research (2023)

Abstract Background: Cell cycle dysregulation is a hallmark of cancer, resulting in unregulated cell proliferation and, eventually, tumor development. Cyclin-dependent kinase 1 (CDK1) is a cell cycle regulatory protein that is involved in cell cycle maintenance. CDK1 has been discovered to be substantially elevated in a several tumors and is linked to poor overall and relapse-free survival. The aim of this study is to understand the regulation role of Helicobacter Pylori infection and inflammation on CDK1 expression in gastric cancer. Methods: Using TCGA data and our integrated comprehensive gene expression analysis, we found a significant overexpression of CDK1 in gastric cancer human and mouse tissues. We detected overexpression of CDK1 in human and mouse gastric glands in response to H. pylori infection. Our data demonstrated that H. pylori infection induced phosphorylation (S536) and activation of NF-kB in vitro and in vivo. Furthermore, H. pylori infection and TNF-α treatment increased the CDK1 mRNA and protein levels in gastric cancer cell lines. Using the ChIP assay, we detected direct biding of NF-κB on the CDK1 promoter regulating its transcription. CDK1 promoted activation of the β-catenin signaling pathway. Using the pTOP/pFOP luciferase reporter assays, as a measure of β-catenin/TCF transcription activity, we confirmed CDK1-dependent activation of β-catenin in response to H. pylori infection. Pharmacologic and genetic inhibition of CDK1 reversed these effects and decreased number and size of gastric tumors organoid from mouse and human. Conclusion: Our findings demonstrate NF-kB-mediated induction of CDK1 expression in response to H. pylori infection with subsequent activation of tumorigenic β-catenin signaling. This novel regulatory link between infection, CDK1, and β-catenin suggests the importance of considering CDK1 inhibitors in gastric cancer. Citation Format: Marwah M. Al-Mathkour, Shoumin Zhu, Longlong Cao, Shayan Khalafi, Zheng Chen, Julio Poveda, Dunfa Peng, Heng Lu, Mohammed Soutto, Tianling Hu, Oliver McDonalnd, Alexander Zaika, Wael El-Rifai. CDK1 bridges NF-kB and b-catenin signaling in response to H. pylori infection in gastric tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5972.
Abstract 195: Establishment and validation of pheochromocytoma organoids for high-throughput drug screening
Authors: Maite Calucho, ZiMing Cheng, Huyen Thi-Lam Nguyen, Ahmad Al Shihabi, Hector Gonzalez-Cantu, Qianjin Guo, Maneesha Thaker, Nicole Bechmann, Graeme Eisenhofer, Yanli Ding, Patricia Dahia, Alice Soragni
Journal: Cancer Research (2023)

Abstract Pheochromocytomas and paragangliomas (PPGL) are rare catecholamine-secreting neuroendocrine tumors known for their genetic diversity. They can be categorized in discrete molecular subgroups, including tumors presenting with pseudohypoxia or kinase signaling activation. Metastatic and recurrent PPGLs have few therapeutic options, in part due to the lack of appropriate study models. Here, we report progress on the establishment of viable organoids from n=10 distinct sporadic or familial PPGLs spanning varios genotypes. We also perform detailed histological, molecular, biochemical, and functional characterization. The ten PPGLs were obtained from patients with distinct clinical history and diverse ethnic and genetic backgrounds. We show how we can generate PPGL organoids from fresh and frozen tissue in a format compatible with histologic characterization and high-throughput drug screening (mini-rings, Phan et al, 2019, Al Shihabi et al, 2022). Our mini ring approach uses fewer cells with no need for expansion in vitro, and is amenable to implement automation for facile high-throughput studies. We can quantify PPGL growth in culture using a machine learning-based pipeline (Al Shihabi et al, 2022). All PPGL organoids for which sufficient number of cells could be obtained grew, regardless of the genotype and molecular subtype. PPGL organoids could be cultured short term (6 days) as well as long term (4 weeks). We investigated cellular composition by staining for the neuroendocrine marker chromogranin A, the sustentacular cell marker S100, and the vascular marker CD34. We also analyzed the expression of catecholamines in the cell culture supernatant by LC/MS/MS. We confirmed that secreted catecholamines matched the primary tumor pattern. Lastly, we present the results of pilot drug screening on both short and long term cultures. Drug sensitivity profiles pinpoint tumor-specific responses. In conclusion, we can establish PPGL organoids that largely recapitulate features of the tumor of origin. These models will provide the ability to investigate tumor initiation and progression for various genetic backgrounds and may reveal novel patterns of drug sensitivity and resistance. Citation Format: Maite Calucho, ZiMing Cheng, Huyen Thi-Lam Nguyen, Ahmad Al Shihabi, Hector Gonzalez-Cantu, Qianjin Guo, Maneesha Thaker, Nicole Bechmann, Graeme Eisenhofer, Yanli Ding, Patricia Dahia, Alice Soragni. Establishment and validation of pheochromocytoma organoids for high-throughput drug screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 195.
Abstract 5570: Development of prognostic index based on twenty-three genes for predicting superficial-to-invasive progression of non-muscle invasive bladder cancer patients
Authors: Jae-Yoon Kim, Seong-Hwan Park, Seon-Young Kim, Seok Joong Yoon, Seon-Kyu Kim
Journal: Cancer Research (2023)

Abstract Background: Although recent advances in high-throughput technology and data-driven approach have provided many insights into non-muscle invasive bladder cancer (NMIBC), previous studies are still limited in their ability to predict the clinical behavior of NMIBC. Here, using deep learning method with long term follow-up data, we identified a prognostic gene set consisting of a small gene group for precisely predicting NMIBC heterogeneity. Methods: We sought to identify progression-associated genes in patients with NMIBC using Cox regression analysis and verified their predictive values using a fully connected neural network (FNN) algorithm in five independent cohorts comprising more than 800 NMIBC patients. Based on these genes, a prognostic index (PI) in NMIBC progression was also developed. The association between the PI and prognosis of NMIBC patients was evaluated using Kaplan-Meier plots and log-rank tests. Results: Gene expression profiling in NMIBC patients identified a prognostic gene set consisting of 1,789 genes for predicting NMIBC progression in a patient cohort (training set, n = 103). Their prognostic significances were validated based on FNN algorithm in other four independent cohorts (validation sets, n = 722). Pathway enrichment analysis revealed a twenty-three gene signature including known prognostic transcription factors such as FOXM1 and E2F1 along with novel genes. We incorporated these genes into the PI system, which was a significant prognostic indicator of NMIBC progression. The PI system was shown to be an independent risk factor by a multivariate analysis and subset stratification according to stage and grade (each P &amp;lt; 0.001). The subset analysis also revealed that the PI system could identify patients who would benefit from BCG immunotherapy. Conclusions: The twenty-three gene-based PI represents a promising diagnostic tool for the identification of high-risk NMIBC patients who would display different clinical behaviours as well as response to BCG immunotherapy. Citation Format: Jae-Yoon Kim, Seong-Hwan Park, Seon-Young Kim, Seok Joong Yoon, Seon-Kyu Kim. Development of prognostic index based on twenty-three genes for predicting superficial-to-invasive progression of non-muscle invasive bladder cancer patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5570.
Abstract 4162: T-cell metabolic profiling with bioluminescent assays
Authors: Maggie Bach, Natasha Karassina, Julia Gilden, Donna Leippe, Mike Valley, Kayla Sylvester, Jolanta Vidugiriene
Journal: Cancer Research (2023)

Abstract Cellular energy metabolism is crucial for cell survival and the balance of metabolic pathways determines the health of the cell. Determining and understanding metabolic profiles of cells can aid in overall insight of cell health and improvement of cell therapeutics, especially for immune interventions. T-cells actively regulate their metabolic profile from quiescent to a highly metabolically active state after activation. Activation rewires the cell to drive glycolysis and oxidative phosphorylation for production of reducing power and ATP for cell growth and proliferation. A small population of these cells then transition to a more quiescent state and persist as memory cells to aid in secondary responses. Although the trend of T-cell metabolism after activation has been studied, the method of investigation is cumbersome and lacks depth of information of overall cell health. To address this, we developed a bioluminescence NAD(P)H core technology and applied it to build a set of cell-based assays covering diverse metabolic pathways including glucose, glycogen, and amino acid metabolism, and the TCA cycle. Here we utilize those assays to investigate changes in metabolic profiles of naïve, effector, and memory T-cells as they transition from a state of oxidative phosphorylation to increased glycolytic rates, dependence on different fuel consumption and storage, including an increase in fatty acid oxidation and glycogen accumulation. We demonstrate flexibility of the assays for detecting multiple metabolites from the same sample and monitoring metabolite changes over time by assaying multiple samples. We show that the assays are amenable to various volumes (96-,384-well plates) and low cell numbers. For example, activity of dehydrogenases involved in glycolysis, pentose phosphate and TCA cycles can be detected with less than 400 cells/well. In conclusion, understanding the processes governing dynamic metabolic changes of T-cells during their transition from naïve to activated to memory phenotypes is required for next-generation cell therapy development. The developed bioluminescence cell-based assays provide the sensitivity, throughput and robustness required for rapid evaluation of such changes. Citation Format: Maggie Bach, Natasha Karassina, Julia Gilden, Donna Leippe, Mike Valley, Kayla Sylvester, Jolanta Vidugiriene. T-cell metabolic profiling with bioluminescent assays. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4162.
Abstract 1747: Targeting metabolic and epigenetic programs to re-sensitize glioblastoma to chemotherapy
Authors: Emma Rowland, Jordan Walter, Anna Jermakowicz, Robert Suter, Rebecca Riggins, Nagi Ayad
Journal: Cancer Research (2023)

Abstract Treatment options for glioblastoma (GBM) are limited. Prognosis remains dismal, with an 18 month on average survival rate following diagnosis due to treatment resistance and disease recurrence. The goal of this project is to investigate hallmarks of cancer progression that contribute to temozolomide (TMZ) resistance, a first tine treatment for GBM. Two signaling pathways were investigated in TMZ-sensitive and -resistant GBM cell lines and in primary and recurrent patient-derived xenograft (PDX) tumor cells by genetically and pharmacologically inhibiting methionine adenosyltransferase 2A (MAT2A) and adenosylhomocysteinase (AHCY). Cell growth and survival were assessed by measuring protein expression of proliferation, oxidative stress and cell cycle arrest markers. EPIC array analysis and targeted bisulfite sequencing were conducted to identify changes in genome-wide and specific CpG island methylation. The Seahorse XF Analyzer measured mitochondrial respiratory capacity and oxidative metabolism. Induced pluripotent stem cell organoids were co-cultured with PDX tumor cells to determine if treatments mitigate tumor cell invasiveness. Compared to parental cells (PC), MAT2A gene expression was increased by 1.7-fold in acquired resistant and de novo resistant GBM cells (RC) [(transcript per million): PC, 7386 ± 412; RC, 12941 ± 1023; n=2; p=2.10e-8].Compared to TMZ-sensitive cells (TS), TMZ-resistant cells (TR) demonstrated a 56% increase in baseline oxygen consumption rate [(pmol/min): TS, 179 ± 6.7; TR, 279 ± 13; n=18; p=.0012] and 64% increase in maximal respiratory capacity [(pmol/min): TS, 403 ± 29; TR, 659 ± 35; n=6; p&amp;lt;.0001]. Both primary and recurrent GBM cells were subject to select MAT2A and AHCY inhibitor compounds and EC50s were determined. Recurrent cells demonstrated a vulnerability to TMZ-generated cell death both by genetically knocking down and pharmacologically inhibiting MAT2A and AHCY. MAT2A and AHCY contribute to TMZ resistance and recurrence by dysregulating methylation programs and upregulating antioxidant programs, respectively. These findings provide a foundation for developing novel combinatory therapeutic strategies and inform clinical studies intended to augment the practically negligible rate of remission for GBM and improve treatment outcomes for cancer patients. Citation Format: Emma Rowland, Jordan Walter, Anna Jermakowicz, Robert Suter, Rebecca Riggins, Nagi Ayad. Targeting metabolic and epigenetic programs to re-sensitize glioblastoma to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1747.
Abstract 4850: High salt diet induced tumor initiating stem cells mediate breast cancer progression
Authors: Lisa Tucker, Sonya Reid, Jeffrey C. Rathmell, Venkataswarup Tiriveedhi
Journal: Cancer Research (2023)

Abstract High-salt (sodium chloride) diets have been associated with several chronic inflammatory diseases. While the role of chronic inflammation in cancer is well established, the specific role of high salt diet in carcinogenesis is unknown. Previous studies with syngeneic murine breast cancer models, both in our laboratory and others, have shown that high salt (HS) diet induced tumor regression through inflammatory activation of anti-tumor adaptive immune responses. We tested this counter-intuitive and suspiciously beneficial role of HS diet by performing sequential passage studies in preclinical murine models. Six week old mice were placed on high salt diet for 2 weeks prior to injection with syngeneic 4T1 and Py230 triple negative breast cancer cells (into BALB/c and C57Bl/6J mice, respectively, referred to as passage-1). Tumors were harvested after four weeks of injection. The cancer cells depleted of immune cells were collected from these harvested tumors and reinjected into new non-tumor bearing mice. This cycle was repeated three times. In passage-1 cohort, by day 28, HS diet induced reduced tumor progression in both 4T1-BALB/c (267 ± 59 mm3) and Py230-C57Bl/6J (238 ± 54 mm3) as compared to regular salt (RS) diet cohort (611 ± 94 mm3 and 473 ± 69 mm3, respectively; p&amp;lt;0.05 for both). However, in passage-4 cohort, by day 28, HS diet induced significantly higher tumor progression in both 4T1-BALB/c (806 ± 91 mm3) and Py230-C57Bl/6J (743 ± 81 mm3) models, as compared to regular salt (RS) diet cohort (577 ± 83 mm3 and 462 ± 77 mm3, respectively; p&amp;lt;0.05 for both). Cellular analysis by flow cytometry revealed that there was a 12-19 fold increase in tumor initiating stems cells (TISCs) in passage-4 HS diet cohort compared to RS diet cohort. Mechanistic studies have demonstrated that there was increased TGFβ expression on TISCs obtained from passage-4 HS diet cohort which correlated with enhanced exhaustion phenotype (CTLA4+) of tumor infiltrating adaptive immune cells (CD4 and CD8 T cells) in this cohort. Co-treatment with anti-TGFβ and anti-CTLA4 monoclonal antibodies (mAb) in passage-4 HS diet cohort, significantly reduced tumor progression (p&amp;lt;0.05), as compared to treatment with either mAb alone. Taken together, these data demonstrated that chronic HS diet leads to expansion of TGFβ expressing TISCs leading to host immune exhaustion and tumorigenesis. Importantly, anti-TGFβ mAb exerted a favorable synergistic effect to enhance the anti-tumor efficacy of immune check-point inhibitors. Citation Format: Lisa Tucker, Sonya Reid, Jeffrey C. Rathmell, Venkataswarup Tiriveedhi. High salt diet induced tumor initiating stem cells mediate breast cancer progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4850.
Abstract 2686: The combination of Cucurbitacin B and Evodiamine inhibits cell migration and propagation, and induces apoptosis in <i>in vitro</i> glioma cells
Authors: Vrutti V. Mehta, Kenza E. Benzeroual
Journal: Cancer Research (2023)

Abstract Glioblastoma is a lethal brain tumor. Despite aggressive treatment, the median survival time is 6 to 12 months. These tumors acquire resistance against many therapeutic regimens. There is a need to screen for potential new drugs and drug combinations. Cucurbitacin B (CuB), a compound obtained from plants, and evodiamine (Evo), a supplement, have shown promising results in various neoplasms but have not been well studied in glioblastoma and especially, as a combination treatment. This study investigated the combined effects of CuB and Evo on U-87MG human glioma cell line. Results demonstrated that CuB and Evo individually decreased the U-87MG cell viability in time and dose dependent manners. The effect was significantly pronounced with the combined treatment. The combination treatment of CuB and Evo induced cellular apoptosis most likely by interfering with the PI3K/AKT and JNK/ERK pathways. In addition, the flow cytometry analysis showed that the combination treatment arrested the cell cycle at the G2M phase and inhibited cell propagation. Moreover, CuB and Evo combined effect successfully inhibited cellular migration. The cytotoxic effect of combination treatment of CuB and Evo was three times lower in neuronal PC-12 cells compared to U-87MG cells. Overall, a combination of cucurbitacin B and evodiamine proved to be a superior potential anti-neoplastic treatment in U-87MG cells as compared to individual treatment, and may be considered as a potential adjuvant therapy for GBM. Citation Format: Vrutti V. Mehta, Kenza E. Benzeroual. The combination of Cucurbitacin B and Evodiamine inhibits cell migration and propagation, and induces apoptosis in in vitro glioma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2686.